This invention relates to a novel calcitonin derivative and a salt thereof having the action of lowering the serum Ca.sup.2+ level and useful as the therapeutic for osteoporosis, bone Paget's disease, digestive hypercalcemia, etc.
Calcitonin (hereinafter called "CT") is a peptide hormone occuring in thyroid glands of various mammals such as human being, or ultrabranchial glands of fish, cyclostomi and birds. The hormone exhibits an action antagonistic to parathyroid hormone, and has been known to act on bone and lower the Ca.sup.2+ level in blood. Up to date, CT has been extracted and purified from human being, bovine, porcine, sheep, rat, chicken, salmon, eel, and its amino acid primary sequence has been clarified. These animal-derived CT are all polypeptides comprising 32 amino acids, and are common in that the cysteine residues at the 1- and 7-positions form a disulfide bond, and the carboxy group terminal end (hereinafter called the "C-terminal") is prolineamide.
These CT are expected to be therapeutics for osteroporosis, bone Paget's disease or digestive hypercalcemia.
However, the disulfide bond possessed by CT is estimated to be very unstable in a solution to bring about probably lowering in physiological activity, and therefore, utilization as a pharmaceutical has been very limited. As a means for solving this problem, a derivative having .alpha.-amino-suberinic acid residue ##STR2## (hereinafter called ##STR3## in place of cystine residue ##STR4## was synthesized. This derivative had high CT activity and yet exhibits high stability in a solution, and was therefore useful as a pharmaceutical.
However, since ##STR5## contains Asu, it involves the problem that its synthesis is complicated, namely can be synthesized only by the liquid phase method in peptide chemistry, and the solid phase method which is the simple and rapid synthetic method is not applicable. Accordingly, in order to obtain a derivative having high activity and high stability, which can be synthesized by the solid phase method, and consequently found that the above object can be accomplished by converting the amino acid residue at the 1-position of calcitonin to a specific cyclic amino acid residue, to accomplish the present invention.
The abbreviated names, the abbreviated symbols to be used in the present specification have the following meanings.